Article
Biochemical Research Methods
Brian F. Kiesel, Robert A. Parise, Anuradha Krishnamurthy, Steven Gore, Jan H. Beumer
Summary: ATR is a master regulator of the DNA-damage response and elimusertib is an ATR inhibitor in development for cancer treatment. Researchers developed an HPLC-MS method to measure elimusertib concentration, which showed good accuracy and precision and can be used to support clinical studies.
BIOMEDICAL CHROMATOGRAPHY
(2022)
Review
Biochemistry & Molecular Biology
Li-Wei Wang, Songwei Jiang, Ying-Hui Yuan, Jilong Duan, Nian-Dong Mao, Zi Hui, Renren Bai, Tian Xie, Xiang-Yang Ye
Summary: This article introduces the importance of ataxia telangiectasia and RAD3-related protein kinase (ATR) in maintaining genomic integrity and its application in cancer therapy. The article also mentions the sensitivity of ATR inhibition to specific tumor mutations and reports on the increasing number of synergistic anticancer effects involving ATR inhibition. The review summarizes the current research progress and provides perspectives on future challenges and opportunities.
Article
Cell Biology
Maria Likhatcheva, Roben G. Gieling, James A. L. Brown, Constantinos Demonacos, Kaye J. Williams
Summary: Genotoxic stress can activate the ATM kinase, with potential involvement of Suv39H1 and Tip60 in ATM activation under hypoxic conditions.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Oncology
R. Kim, M. Kwon, M. An, S. T. Kim, S. A. Smith, A. B. Loembe, P. G. S. Mortimer, J. Armenia, N. Lukashchuk, N. Shah, E. Dean, W. -Y. Park, J. Lee
Summary: Ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and shows stable and sustained disease control rate.
ANNALS OF ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Chloe Gulliver, Ralf Hoffmann, George S. Baillie
Summary: The DNA damage response is crucial for maintaining genomic integrity and is often hijacked by cancer cells. Targeting ATM and ATR can enhance the treatment of prostate cancer and reduce therapeutic resistance.
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Yunxin Duan, Haodong Cheng, Lili Zhuang, Jiawei Xia, Yerong Xu, Ruyue Zhang, Rui Sun, Tao Lu, Yadong Chen
Summary: ATR kinase is crucial in the DNA damage response and its inhibition could induce synthetic lethality (SL) with DDR deficiencies. We developed a series of selective and potent ATR inhibitors with a thieno[3,2-d]pyrimidine scaffold. Compound 34 was identified as a representative molecule that effectively inhibited ATR kinase and showed antiproliferative effects against cancer cells. Compound 34 also demonstrated good pharmacokinetic properties, in vivo antitumor efficacy, and no obvious toxicity, making it a promising lead compound for drug development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Genetics & Heredity
Motohiro Yamauchi
Summary: Chromosome rearrangements are structural variations in chromosomes and are associated with a variety of human diseases. Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by chromosome rearrangements at the cellular level, particularly in T lymphocytes. The defective gene in A-T is ataxia-telangiectasia mutated (ATM), which plays a central role in cellular response to DNA damage, including suppressing chromosome rearrangements.
Article
Oncology
Jingyu Xun, Hideo Ohtsuka, Katsuya Hirose, Daisuke Douchi, Shun Nakayama, Masaharu Ishida, Takayuki Miura, Kyohei Ariake, Masamichi Mizuma, Kei Nakagawa, Takanori Morikawa, Toru Furukawa, Michiaki Unno
Summary: This study reveals the impact of ATM expression on the prognosis of pancreatic cancer patients. Loss of ATM expression enhances tumor development, suppresses apoptosis, and reduces sensitivity to gemcitabine. Additionally, loss of phosphorylated ATM is associated with poor prognosis in pancreatic cancer patients.
Article
Immunology
Raissa Bernardes da Silva, Willian dos Reis Bertoldo, Lucila Langoni Naves, Fernanda Bernadelli de Vito, Jeziel Dener Damasceno, Luiz Ricardo Orsini Tosi, Carlos Renato Machado, Andre Luiz Pedrosa
Summary: In this study, the DNA damage response pathways in promastigote forms of L. major were investigated. The overexpression of LmjEXO1 made the cells more susceptible to genotoxic damage, while ATR-specific inhibition made the control cells more susceptible to oxidative damage.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Medicine, Research & Experimental
He Cheng, Er-shao Zhang, Xiao Shi, Ping-ping Cao, Bei-jing Pan, Xin-xin Si, Yue Liu, Nan Yang, Ying Chu, Xu-chun Wang, Xiao Han, Zhi-hong Zhang, Yu-jie Sun
Summary: This study confirmed that ATM-AS significantly upregulated ATM gene activity by recruiting KAT5 histone acetyltransferase to the gene promoter. Decreased ATM-AS levels led to abnormal downregulation of ATM expression and impaired ATM-mediated DNA damage repair in normal breast cells in vitro. The level of ATM-AS was positively correlated with ATM expression and patient prognosis in breast cancer tissue samples.
CURRENT MEDICAL SCIENCE
(2022)
Article
Chemistry, Medicinal
Huachao Bin, Pei Chen, Ming Wu, Falu Wang, Guifeng Lin, Shulei Pan, Jingming Liu, Bo Mu, Jinshan Nan, Qiao Huang, Linli Li, Shengyong Yang
Summary: This study reports the discovery of a potent and highly selective ATR inhibitor, SKLB-197, which demonstrated strong activity against ATR and weak or no activity against other protein kinases. SKLB-197 showed significant antitumor activity against ATM-deficient tumors both in vitro and in vivo, and it exhibited favorable pharmacokinetic properties. These findings suggest that SKLB-197 could be a promising lead compound for drug discovery targeting ATR.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Physiology
Rachel Warren, Andrew M. Dylag, Molly Behan, William Domm, Min Yee, Margot Mayer-Proschel, Luis Martinez-Sobrido, Michael A. O'Reilly
Summary: Children and young adults with mutant forms of the ATM gene, which is involved in DNA damage signaling and mitochondrial homeostasis, suffer from respiratory infections, immune deficiencies, and obstructive airways disease associated with disorganized airway epithelium. A study on mice showed that ATM is required for the regeneration of injured airway epithelium after influenza virus infection. Mice lacking ATM exhibited increased airway resistance and reduced lung compliance during infection, and their lungs developed an abnormal proximal airway epithelium containing cells lacking expression of the immunomodulatory protein Scgb1a1. Restoration of Scgb1a1 expression in the airways required ATM and failure to efficiently restore it may contribute to the respiratory diseases seen in individuals with ataxia telangiectasia.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2022)
Article
Allergy
Ismail Ogulur, Tugce Ertuzun, Burcu Kocamis, Yasemin Kendir Demirkol, Emel Uyar, Ayca Kiykim, Dilek Baser, Gozde Yesil, Hacer Akturk, Ayper Somer, Ahmet Ozen, Elif Karakoc-Aydiner, Meltem Muftuoglu, Safa Baris
Summary: Heterozygous relatives of ataxia-telangiectasia (AT) patients are at increased risk for certain AT-related manifestations, and parents of AT patients show an increase in infection frequency. It is hypothesized that parents may exhibit immune alterations similar to their affected children.
PEDIATRIC ALLERGY AND IMMUNOLOGY
(2021)
Article
Genetics & Heredity
Mohammad Z. Islam, Xinggui Shen, Sibile Pardue, Christopher B. Pattillo, Christopher G. Kevil, Rodney E. Shackelford
Summary: The ATM protein plays a crucial role in regulating cell cycle checkpoints, cellular redox state, and DNA repair. Its loss in ataxia-telangiectasia (A-T) leads to symptoms such as ataxia, telangiectasias, dysregulated redox and iron responses, and increased cancer risk. Our study reveals that ATM regulates the sulfur pool, Fe-S cluster biosynthesis, transsulfuration pathway, and glutathione redox cycling, which may explain some of the redox- and iron-related pathologies seen in A-T.
Article
Oncology
Seung Tae Kim, Simon A. Smith, Peter Mortimer, Arsene-Bienvenu Loembe, Heejin Cho, Kyoung-Mee Kim, Claire Smith, Sophie Willis, Itziar Irurzun-Arana, Alienor Berges, Jung Yong Hong, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Iwanka Kozarewa, Andrew J. Pierce, Emma Dean, Jeeyun Lee
Summary: Ceralasertib in combination with paclitaxel showed tolerability and antitumor activity in patients with advanced malignancies, with durable responses observed in advanced melanoma patients resistant to anti-PD1/L1 treatment.
CLINICAL CANCER RESEARCH
(2021)
Article
Biology
Duc M. Nguyen, Palak R. Parekh, Elizabeth T. Chang, Navesh K. Sharma, France Carrier
RADIATION RESEARCH
(2015)
Article
Oncology
Elizabeth T. Chang, Palak R. Parekh, Qingyuan Yang, Duc M. Nguyen, France Carrier
Article
Biochemical Research Methods
Katherine Coburn, Zephan Melville, Ehson Aligholizadeh, Braden M. Roth, Kristen M. Varney, France Carrier, Edwin Pozharski, David J. Weber
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2017)
Article
Oncology
Ivana Gojo, Ming Tan, Hong-Bin Fang, Mariola Sadowska, Rena Lapidus, Maria R. Baer, France Carrier, Jan H. Beumer, Bean N. Anyang, Rakesh K. Srivastava, Igor Espinoza-Delgado, Douglas D. Ross
CLINICAL CANCER RESEARCH
(2013)
Article
Biochemistry & Molecular Biology
Jing Lin, Qingyuan Yang, Paul T. Wilder, France Carrier, David J. Weber
JOURNAL OF BIOLOGICAL CHEMISTRY
(2010)
Article
Biochemistry & Molecular Biology
Kotb Abdelmohsen, Kumiko Tominaga, Eun Kyung Lee, Subramanya Srikantan, Min-Ju Kang, Mihee M. Kim, Roza Selimyan, Jennifer L. Martindale, Xiaoling Yang, France Carrier, Ming Zhan, Kevin G. Becker, Myriam Gorospe
NUCLEIC ACIDS RESEARCH
(2011)
Article
Multidisciplinary Sciences
Fred E. Indig, Ivana Rybanska, Parimal Karmakar, Chakravarty Devulapalli, Haiqing Fu, France Carrier, Vilhelm A. Bohr
Review
Genetics & Heredity
Narasimharao Nalabothula, France Carrier
Article
Biochemistry & Molecular Biology
Eduardo Solano-Gonzalez, Katherine M. Coburn, Wenbo Yu, Gerald M. Wilson, Elmar Nurmemmedov, Santosh Kesari, Elizabeth T. Chang, Alexander D. MacKerell, David J. Weber, France Carrier
Summary: The chemical probes identified in this study target hnRNP A18 RNA Recognition Motif (RRM), leading to disruption of hnRNP A18-RNA interactions and downregulation of key proteins, ultimately inhibiting cancer cell proliferation without affecting normal cell viability. The findings highlight the potential of post-transcriptional regulation of immune checkpoints as a therapeutic strategy in cancer treatment.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Paul T. Wilder, Jing Lin, Catherine L. Bair, Thomas H. Charpentier, Dong Yang, Melissa Liriano, Kristen M. Varney, Andrew Lee, Amos B. Oppenheim, Sankar Adhya, France Carrier, David J. Weber
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2006)
Article
Oncology
MS Kim, JH Baek, D Chakravarty, D Sidransky, F Carrier
EXPERIMENTAL CELL RESEARCH
(2005)
Article
Chemistry, Medicinal
J Markowitz, J Chen, R Gitti, DM Baldisseri, YP Pan, R Udan, F Carrier, AD MacKerell, DJ Weber
JOURNAL OF MEDICINAL CHEMISTRY
(2004)
Article
Biochemistry & Molecular Biology
RQ Yang, DJ Weber, F Carrier
NUCLEIC ACIDS RESEARCH
(2006)
Review
Chemistry, Medicinal
J Markowitz, AD MacKerell, F Carrier, TH Charpentier, DJ Weber
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2005)